Haematology for Doctors

Category: Chronic Myeloid Leukaemia (CML)

  • Chronic Myeloid Leukaemia (CML) – A Junior Doctor’s Guide

    Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder characterised by the uncontrolled proliferation of myeloid cells in the bone marrow. It is unique among leukaemias due to its strong association with a specific genetic abnormality, the Philadelphia chromosome (t(9;22)), which leads to the formation of the BCR-ABL fusion gene. This guide provides an overview of CML for junior doctors rotating through haematology.

    Understanding CML

    CML is a triphasic disease with distinct clinical phases:

    • Chronic Phase – Most patients are diagnosed in this phase, which is typically indolent and well-managed with targeted therapy.
    • Accelerated Phase – Increased disease activity with worsening cytopenias, rising white cell counts, and worsening symptoms.
    • Blast Crisis – Resembles acute leukaemia, with a poor prognosis unless treated aggressively.

    Clinical Presentation

    CML is often detected incidentally on routine blood tests. However, symptomatic patients may present with:

    • Fatigue and weight loss – Due to increased metabolic activity.
    • Splenomegaly – Leading to early satiety, left upper quadrant pain, or abdominal discomfort.
    • Night sweats and fever – Indicative of disease progression.
    • Bone pain – Due to increased myeloid proliferation.
    • Bleeding/bruising – If thrombocytopenia develops in later stages.

    Investigations

    A structured diagnostic approach is key when CML is suspected:

    • Full Blood Count (FBC) & Blood Film – Shows leucocytosis with a left shift (neutrophils, myelocytes, basophilia, and eosinophilia).
    • Bone Marrow Aspirate & Biopsy – Hypercellular marrow with increased granulopoiesis.
    • Cytogenetics & Molecular Testing –
      • Philadelphia chromosome detection via karyotyping.
      • BCR-ABL1 fusion gene confirmed via PCR or fluorescence in situ hybridisation (FISH).
    • Lactate Dehydrogenase (LDH) & Uric Acid – Markers of high cell turnover.

    Management

    Treatment of CML has been revolutionised by the introduction of tyrosine kinase inhibitors (TKIs), which specifically target the BCR-ABL fusion protein.

    Supportive Care

    • Hydroxyurea – Used for cytoreduction in patients with very high white cell counts at diagnosis.
    • Allopurinol & Hydration – To prevent tumour lysis syndrome (TLS).

    Definitive Treatment

    1. Tyrosine Kinase Inhibitors (TKIs) – The cornerstone of CML treatment, including:
      • First-line: Imatinib (first-generation), Dasatinib, Nilotinib (second-generation).
      • For resistant disease: Bosutinib, Ponatinib (third-generation).
      • TKI response monitoring: Measured via BCR-ABL1 transcript levels using quantitative PCR.
    2. Stem Cell Transplantation – Considered for TKI-resistant disease or blast crisis.
    3. Chemotherapy – Used in blast crisis to induce remission before transplant.

    Palliative Care

    • For patients who fail multiple lines of therapy or are unfit for aggressive treatment, supportive care focuses on symptom management and maintaining quality of life.
    • Palliative options include hydroxyurea for cytoreduction and symptom control.
    • End-of-life discussions and advanced care planning should be initiated when disease progresses despite therapy.

    Complications to Watch For

    • Disease Progression – Transition from chronic to accelerated phase or blast crisis.
    • TKI Resistance or Intolerance – Requires switching therapy or alternative treatment strategies.
    • Cardiotoxicity & Vascular Events – Seen with second- and third-generation TKIs.
    • Myelosuppression – TKI-induced cytopenias may require dose modifications.
    • Tumour Lysis Syndrome (TLS) – Can occur at treatment initiation, requiring prophylactic measures.

    Prognosis and Follow-Up

    • With TKIs, CML has transformed into a manageable chronic condition with near-normal life expectancy if well-controlled.
    • Regular monitoring with BCR-ABL1 PCR ensures response to therapy and detects early resistance.
    • Some patients in deep remission may attempt treatment-free remission (TFR) under strict monitoring.

    Key Takeaways for Junior Doctors

    1. CML is strongly linked to the Philadelphia chromosome (t(9;22)) and BCR-ABL fusion gene.
    2. Tyrosine kinase inhibitors (TKIs) have revolutionised treatment and significantly improved survival.
    3. Monitoring BCR-ABL1 transcript levels via PCR is crucial for assessing treatment response.
    4. Recognising disease progression from chronic phase to blast crisis is critical.
    5. Palliative care is an important option for patients who are refractory to treatment or unfit for aggressive therapy.

    CML is a fascinating disease that exemplifies the power of targeted therapy in modern haematology. Understanding its phases, management, and complications will help junior doctors provide optimal patient care.

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